DE2711095C2 - Bis-trimethylsilylcefamandol, process for its manufacture and its use for the manufacture of cefamandol - Google Patents

Description

Cefamandol is a cephalosporin antibiotic that is used to treat infectious diseases let fight, such as enterobacterial infections (US-PS 39 03 278). Cefamandol is 7- (D-MandeIamido) -3- (imethyl-l ^ / t-tetrazol-S-ylJthiomethyl-l-cephem ^ -carboxylic acid and is first used in US Pat. No. 3,641,021, Example 5.

The process for the preparation of cefamandol by acylating 7-amino-3- (l-methyl-1,2,3,4-tetrazol-S-ylJthiomethyl-S-cephem ^ carboxylic acid / Cefamandolkern) with D-O-carboxymandelic anhydride is described in U.S. Patent 3,840,531. The silylation of a Cephalosporin nucleus is disclosed in US Pat. No. 3,671,449. From US-PS 36 94437 the acylation is one silylated cephalosporin nucleus known In DE-OS 25 22 997 (Derwent 81950W / 50) 7- (D-alpha-Hy-

droxyphenylacetamidoJ-S-ie-hydroxypyridazin-S-yl- or -tetrazoloM ^ -bZ-pyridazin-e-yOthiomethyl-S-cephem-4-carboxylic acids which are protected on alpha-hydroxyl and carbonic acid functions

Cefamandol can only be used in raw form extremely difficult to purify by recrystallization, so that it is very difficult to manufacture a product which is sufficiently pure for pharmaceuticals The object of the invention is therefore to provide a new and simple means and way of production of pure cefamandole, and this object is now achieved in the manner that emerges from the claims.

It is already known to work with silyl groups which can be easily removed as protective groups. However, silylated cephalosporins are generally so unstable that only relatively few such compounds have been characterized as such

According to the invention there is now a stable crystalline Cefamandolsilylderivat, namely BL · irimethylsilylcefamandol, created, which can be easily converted into cefamandolic acid of excellent purity

The ones required for the process according to the invention Reagents are either commercially available or described in the literature. Both N-trimethylsolylacetamide and N, O-bis (trimethylsilyl) acetamide are im Commercially available. The preparation of the D-anhydro-O-carboxymandelic acid required as an acylating agent

C ₆ H ₅ -

ι I

O O

is described in US Pat. No. 3,840,531, Example V.

The predominant hydrolysis product of bis-trimethylsilylcefamandot is a metastable pentahydrate, the can be easily converted into the more stable trihydrate.

The cefamandol hydrate can easily be converted into sodium cefamandol of high purity by using it reacts with sodium 2-ethylhexanoate or sodium acetate

The bis-trimethylsolylcefamandol according to the invention can be prepared from the cefamandole core of the formula IH by first silylating the core and then acylated with D-anhydro-O-carboxymandelic acid, for which one works in practically anhydrous ethyl acetate. The silylated acetamide compounds are called Siyliermitte! preferred. N-trimethylsilylacetamide (MSA) and N, O-bis (trirwethylsilyl) acetamide (BSA) are particularly preferred. Practically anhydrous is understood to mean that only trace amounts Water are allowed which the primary reaction does not significantly affect. For complete silylation of the core to form the compound of Formula IV requires two trimethylsilyl equivalents. The silylation of the core is preferably carried out under Use of two molar equivalents of MSA or

ίο an equivalent BSA or a small surplus carried out therefrom. When technical MA is used, four molar equivalents are preferably used for the silylation.

The silylation reaction is exothermic, so that the

Temperature of the reaction mixture, if one carries out the silylation at ambient temperature rises to about 40 ⁰ C. The reaction, however, can be generally carried out at temperatures between 0 ⁰ C and 8O ⁰ C, preferably at the other working temperature The silylation is running rapidly at ambient temperature, and the siliconized cefamandole goes into solution. After resolving the Primary reactants are acylated the silylated nucleus preferably with one molar equivalent or one

slight excess of D-anhydro-O-carboxymandelic acid. The acylation can be carried out by the silylated core is added to the acylating agent or the silylated core is mixed with the acylating agent As the acylation progresses, the compound falls off Formula I from the solution and can be filtered by filtration be won.

A surprising result of the present process is the fact that the silylated product accrues as crystalline material, which against moisture

speed is stable and can be stored in cefamandol hydrate until a later transformation

The bis-trimethylsilylcefamandol of the formula I obtained by one of the processes described above can be can be converted into cefamandole by hydrolysis.

Alternatively, the compound of the formula I can also first be converted into an isopropyl solvate by solvolysis and this can then be converted under very mild conditions Hydrolyze cefamandol. In both cases, the primary product of hydrolysis is cefamandoipentahy However, drat cefamandol pentahydrate is a metastabi les material from which the more stable trihydrate is readily formed by heating or prolonged drying Expediently, the hydrolysis product obtained is therefore transferred straight through

Dry into the cefamandole trihydrate

The hydrolysis is preferably carried out in aqueous solvent mixtures, since bis-trimethylsilylcefamandol is practically insoluble in water. the Silyl compound can be mixed with water and

Convert ethanol or isopropanol. The hydrolysis is best carried out by heating the silyl compound in these solvent mixtures to the boiling point After heating has gone into solution, hydrolysis is in progress quickly and within a short period of time, is ordinary finished within minutes. The pentahydrate compound obtained can be by evaporation of the Obtain solvent under vacuum or crystallize from the solution by cooling. By connecting After drying, the pentahydrate becomes more stable Cefamandol trihydrate transferred.

Bis-trimethylsilylcefamandol can also be used with mixtures of isopropanol and a primary alcohol

from the group consisting of methanol, ethanol, propanol or butanol, which results in an isopropyl solvate obtained by subsequent reaction of the resulting cefamand isopropyl solvate with water this can easily be converted into cefamandole. You can also use the hydrolysis product here win again as cefamandol pentahydrate and then convert this material into the trihydrate on drying convict.

The invention is further illustrated by the following examples

example 1

Production of bis-trimethylsilylcefamarido! over the Cefamandolkern

gg (24.4 mmol) 7-amino-3- (l-methyI-l, 23,4-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid of the formula III, 12.8 g (97, 6 mmol) N-trimethylsilylacetamide and 100 inl ethyl acetate are stirred together at room temperature until the reactants dissolve. The reaction mixture obtained in this way is then mixed with D-anhydro-O-carboxymandelic acid, 4.77 c (26.8 mmol ), in the form of a solution in ethyl acetate. The reaction mixture is stirred for 2 hours and then seeded with bis-trimethylsilylcefamandol. The product which precipitates out of the solution is filtered off. The crude product is washed with water to remove acetamide and then dried. Subsequent recrystallization of this material from a mixture of methylene chloride and n-hexane gives bis-trimethylsilylcefamandol in 30 percent yield. Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): Delta 0.12 and 037 (18, s, TMS), 3.80 (2, s, C-2 methylene), 3.91 (3, s, NCH ₃ ), 4, 48 (2, d, C-3 methylene), 5.05 (1, d, J = 5 Hz, C-6), 516 (1, s, alphaH), 5.81 (1, q, J = 5 & 10 Hz, C-7), 7-NH).

Example 2

Production of bis-trimethylsilylcefamandol via the silylated cefamandol core

8 g (24.4 mmol) of cefamandole nucleus of the formula III are added at a temperature of 60 ° C. with 12.8 g (97.6 mmol) of N-trimethylsilylacetamide in 45 ml of ethyl acetate until everything has gone into solution the reaction mixture is cooled to room temperature. The thus obtained »ΐ solution of the silylated Kern is then added to 2.82 g (15.8 mmol) of D-anhydro-O-carboxymandelic acid at ambient temperature in 35 ml of ethyl acetate and stir the whole for 2 hours. The insoluble product obtained is filtered off and dried under vacuum. To remove acetamide, the silyl product is then washed in 300 ml Water. Subsequent drying of the material leads to 7.4 g of bis-trimethyisilylcefamandol, whose NMR spectrum corresponds to the product of Example 1

Example 3 A. Cefamand Isopropyl Solvate

23.2 g of bis-trimethylsilylcefamandol are dissolved under Boil in 75 ml of ethanol. The homogeneous solution obtained is diluted with 500 ml of isopropanol, whereupon they are allowed to cool and evaporated in vacuo. The residue obtained in this way is dissolved in 250 ml of isopropanol dissolved, whereupon the solution is filtered, cooled and then filtered again, resulting in 14.85 g of cefamand isopropyl solvate-

NM R spectrum (acetone / d ₆ ): Delta 1.22 (6, d, J = 6 Hz, (CH ₃ J _{2 of} the solvate), 3.85 (2, s, C-2 methylene), 4, 07 (4, s and m, N-CH ₃ and CH of the solvate), 4.51 (2, s, C-3 methylene), 5.27 (I, d, J = 5 Hz, C-6), 5.37 (1, s, alphaH), 5.95 (I, q, J = 5 & 10 Hz ₁ C-7), 737 (2, s, OH of the solvate and alphaOH), 75 (5, m , aromatic) and 8.23 ppm (I, d, J = 10 Hz, 7-NH).

B. Conversion of cefamand isopropyl solvate
in cefamandole trihydrate

3.85 g of the cefamand isopropyl solvate obtained according to Example 3A are stirred in a mixture for 1 hour Water (300 ml) and ice. The insoluble product is then filtered off and dried under vacuum giving 3.1 g of material. A powder sample of this product is subjected to X-ray analysis. The X-ray diffraction spectrum obtained in this way corresponds to an authentic sample of cefamandole trihydrate. The NMR spectrum is similar to that of Pentahydrates from Example 5.

B e i s ρ i e I 4

Cefamandol pentahydrate

1 g of bis-trimethylsilylcefamandol is dissolved under Boil and heat in aqueous solution for 10 minutes

jo ethanol (2 ml water, 25 ml ethanol). The solution is diluted with 50 ml of water and then cooled. In this way, 03 g of crystalline cefamandol pentahydrate is obtained. Nuclear Magnetic Resonance Spectrum (acetone / de): Delta 3.76 (2, s, C-2 methylene), 4.0 (3, s, N-CH ₃ X435 (13, s, 5 H2O + C-3

J ₅ methyler. + AlphaOH) 5.11 (1, d, J = Hz, C-6), 5.22 (I, s, alphaH), 5.80 (1, q, J = 5 & 10 Hz, C-7), 7.42 (5, m, aromatic) and 8.17 ppm (1, d, J = 10 Hz, 7-NH).

w B eis ρ ie 1 5

Production of bis-trimethylsilylcefamandol
Upper Cefamandol

4 g (8.6 mmoles) of cefamandol, 5.4 g (34.4 mmoles) of N-trimethyisilylacetamide and 50 ml of ethyl acetate are stirred for 2 hours at room temperature. The unusual one The product is filtered off and dried under vacuum. This pipe product is then washed with water, dried and recrystallized from a mixture of so chloroform and η-hexane, whereby one 33 g (63 ^%) bis-trimethylsilylcefamandol of the formula I. obtained whose NMR spectrum is identical to the product of Example 1.

Example 6

Manufacture of bis-trimethylsilylcefamandol
about BSA

454 g (0.98 mol) of cefamandol are added to a solution of 219.79 g (1.08 mol) of N, O-bis (trimethylsilyi) acetamide in 2300 ml of ethyl acetate. Within a few minutes, the silyl derivative begins to crystallize out of the solution. The reaction mixture is stirred for about 2 hours. Subsequent filtering off the insoluble product gives 412.2 g (69.4%) of bis-trimethylsily'cefamandol, which is identical to the product of Example 1.

Example 7

Manufacture of ßis-methylsilylcefamandol
via N-methylsilylimida / .ol

1OmMoI (4.62 g) of cefamandole is added to a solution of ethyl acetate (25 ml) and 4 ml (3, umWoI) N-trimethylsilylimidazole. After dissolving the reactants the product begins to fail. The reaction mixture is stirred for 1 hour. Then will the insoluble product filtered off and washed with Äthyheetat as well as ether washed. By then drying the product obtained in this way under vacuum one arrives at b.Ofe g (45%) bis-tninethvlsilvlcfamandol, which is identical to the product of Example I.

Example 8

Manufacture of bis-triniethylsilyleefamaridol
via N ₁ O-bis (trimethylsilyl) trifluoroacetamide

2.5 g (5.4 mmol) of cefamandole are added to a Mixture of ethyl acetate (15 ml) and 1.5 ml of N, O-bis (trimethylsilyl) trifluoroacetamide. The reaction mixture is stirred for 2 hours. The thereby precipitated product is filtered off and dried under vacuum, whereby 2.0 g (61%) of bis-trimethylsilylcefamandol are obtained. A sample of this product gives an NMR spectrum which is identical to the product of Example I.

Claims (2)

Patent claims: 1. Bis-trimethylsilylcefamandol of the formula I. C ₆ H ₅ CHC-NH OSi (CHj) ₃ (D 2. Process for the preparation of bis-trimethylsilylcefamandol of the formula I ₁ mentioned in claim 1, characterized in that one in each case known way the cefamandol core of the formula III H ₂ N N- CH, S- -N N vfyj / CH ₃ (Π1) with a silylating agent from the group N-trimethylsilylimidazole in practically anhydrous ethyl acetate silylacetamide, N, O-bis (trimethylsilyl) acetamide, N ₁ O-jo and the obtained in this way Bis (trimethylsilyl) trifluoroacetamide, N-trimethylsilylated cefamandol nucleus of the formula IV silyl-N-methyltrifluoroacetamide or N-trimethyl- (CHj) ₃ Si-NH N N CH ₂ S- COOSi (CH ₃ ) J. Il CH ₃ (IV) then acylate with D-anhydro-O-carboxymandelic acid in practically anhydrous ethyl acetate 3. Use of bis-trimethylsilylcefamandol the formula I given in claim 1 for Manufacture of cefamandol of formula II OC ₆ H ₅ CHC-NH HO N- CH ₂ S- COOH (Π) characterized in that one bis-trimethylsilylcefamandol either (a) treated with a mixture of water and ethanoi or isopropanol or (b) with a mixture of isopropanol and a primary alcohol from the group methanol, Ethanol, propanol or butanol treated to form cefamandolisopropyl solvate and this isopropyl solvate then reacts with water, and the cefamandol obtained in this way is obtained as a hydrate.